Coronaviruses (CoV) are RNA viruses that cause gastrointestinal, respiratory, and neurological symptoms in several mammalian species. The outbreak of the severe acute respiratory syndrome CoV (SARS-CoV) in humans 2002 was fatal in ~10% of infected patients, infecting ~8000 people and killing 800. The recent incidents involving the highly pathogenic Middle East Respiratory Syndrome CoV (MERS-CoV) demonstrate that the emergence of pathogenic CoVs from animals to humans can occur at any time. There are currently no FDA approved drugs available for treatment of either SARS or MERS; thus, the development of therapeutic agents to treat CoV infections is an essential, unmet medical need. Because entry into host cells is the first step in the viral life cycle, this aea offers a major target for treatment and prevention. CoVs encode three surface proteins, and the spike S protein must be proteolyzed by human cathepsin L (CatL) for proper entry. The fact that several CoVs utilize this key human protease, CatL, for entry offers an opportunity to develop pan-anticoronavirus inhibitor drugs. We aim to generate potent, specific lead inhibitors for CatL via exploration of the prime side a-helical binding pocket that results in inhibition of SARS-CoV and MERS-CoV infection in live cell assays, and to analyze ADME/toxicology properties en route to testing in animal models of CoV infection.